Modulation of Pulmonary Dendritic Cell Function during Mycobacterial Infection

Abstract

We have previously reported that during mycobacterial infection, naïve CD4؉ T-cell activation is enhanced in the lungs. We investigated the role of chemokine receptor CCR7 and its ligands in the ability of CD11c؉ lung dendritic cells (DCs) to activate naïve CD4 ؉ T cells during pulmonary infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG). BCG infection resulted in the accumulation and maturation in the lungs of DCs that persisted as the mycobacterial burden declined. Lung DCs from infected mice expressed more major histocompatibility complex class II (MHC-II) than those from uninfected mice. CCR7 expression levels on lung DCs were comparable among uninfected and infected mice. The gene expression of the CCR7 ligand CCL19 progressively increased throughout BCG infection, and its expression was MyD88 dependent. CD11c؉ lung cells from BCG-infected mice activated ovalbumin (OVA)-specific naïve CD4؉ T cells more than CD11c ؉ lung cells from uninfected mice. Interestingly, during peak mycobacterial infection, CD11c hi MHC hi lung DCs had slightly decreased chemotaxis toward the CCR7 ligand CCL21 and less efficiency in activating naive CD4 ؉ T cells than DCs from mice during late-stage infection, when few bacilli are found in the lung. These findings suggest that during BCG infection, the inflammation and sustained expression of CCL19 result in the recruitment, activation, and retention in the lung of DCs that can activate naïve CD4 ؉ T cells in situ.During pulmonary mycobacterial infection, the migration of dendritic cells (DCs) and the dissemination of mycobacteria to draining lymph nodes are thought to be important for a successful cell-mediated immune response (6,22,36). Upon the engagement of Toll-like receptors (TLRs) on DCs by mycobacterium-derived, pathogen-associated molecular patterns, DCs undergo a coordinated maturation program that upregulates expression of the chemokine receptor CCR7. Chemokine receptor CCR7 expression is essential for the migration of DCs to the lymph nodes, where they coordinate adaptive immune responses following TLR stimulation (9,17,23,33,34).CCR7 and its ligands, CCL19 (Epstein-Barr virus-induced molecule 1 ligand chemokine) and CCL21 (secondary lymphoid chemokine), are important for both the initiation and regulation of adaptive immunity, as they direct the migration of mature DCs, naïve CD4 ϩ T cells, and central memory T cells to secondary lymphoid organs (SLOs) (31, 32). There are two isoforms of CCL21: CCL21-ser and CCL21-leu. CCL19 and CCL21-ser are produced by stromal cells within the T-cell zones of SLOs. CCL21-ser is also expressed in high endothelial venules, while CCL21-leu is expressed only in the lymphatic endothelium. Upon maturation, DCs also express CCL19 (26). Both CCL19 and CCL21 are involved in the organization of lymphoid structures under normal and chronic inflammatory conditions by facilitating encounters among stromal cells, T cells, B cells, and DCs (1,20,21).CCR7 may have a restricted role in immune responses to airborne pathogens. Mice lackin...

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